Summary An excess incidence of thyroid cancer has been identified among World Trade Center (WTC) rescue and recovery workers included in the WTC Health Program (WTCHP) at Mount Sinai in New York. An excess has also been reported among participants of two separate WTC-exposed cohorts. It is unclear whether the excess is associated with WTC-related exposures or represents an artifact due to increased surveillance. Current understanding of the etiology and pathogenesis of thyroid cancer is limited, and an association between this cancer and WTC-related exposures would add significant information for the health of WTC responders and beyond. Conversely, the finding that excess risk among WTCHP participants is not attributable to WTC related exposures, but to over- diagnosis because of enhanced surveillance, perhaps related to the increased number of chest imaging due to respiratory problems in this population, would represent an important message to WTCHP members. The objectives of this project are to elucidate the reasons for the increased incidence of thyroid cancer among WTCHP participants and to explore the behavior of these cancers. Specifically, the project will investigate clinical and epidemiological characteristics of thyroid cancer in WTC responders and compare them to those of matched non-WTC thyroid cancers: tumor size, nodal involvement, local and distant metastatic spread, previous history of chest imaging, frequency of medical visits, diagnosis because of symptoms vs. asymptomatic finding during medical surveillance will be compared between the two groups of patients. The prevalence of tyroid cancer risk factors will also be compared between the two groups. The second task of this project is to identify in thyroid tissue samples markers of malignancy that were found to be able to accurately discriminate between benign and malignant thyroid follicular carcinoma. This approach will identify and eliminate false positives for the diagnosis of malignancy. Although there is always an area of uncertainty when scoring a thyroid cancer as malignant, we hypothesize that a false diagnosis of malignancy is more likely to occur among WTC responders than in non WTC thyroid cancers, because of increased surveillance and a more conservative approach towards this population. Upon completion of this study, if the increased incidence appears to be real, the result could have important implications in terms of surveillance and care; if the effects of excess surveillance are proven, that would argue for a decrease in the intensity of screening. In both cases, the project will have important implications on the surveillance and clinical management of thyroid cancer, a frequent cancer among WTCHP members.